About KRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KRAS c.34_35delinsTGTGC, p.(Gly12delinsCysAla)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen KRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
The variant affects codon 12 within the P-loop domain (amino acids 10-17), a critical and well-established functional domain per the RASopathy VCEP supplementary table. Codon 12 is a known mutational hotspot with no benign variation in this region. Hotspot analysis confirms this residue is statistically significant.
PM2Supporting
PM2 · supporting
This variant is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per RASopathy VCEP v2.3.0, PM2 is applied at Supporting strength when the variant is absent from gnomAD controls.
PM4Moderate
PM4 · moderate
This is an in-frame deletion-insertion (c.34_35delinsTGTGC) resulting in a protein length change (p.Gly12delinsCysAla). KRAS has no known repetitive regions per the RASopathy VCEP. PM4 is applied at Moderate strength per VCEP rule: 'No known repetitive areas in gene. Use as described.'
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PM2 supporting, PM4 moderate; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen KRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant resides at codon 12 within the P-loop domain (AA 10-17), a critical functional domain per RASopathy VCEP specifications. Codon 12 is a well-established mutational hotspot with no benign variation. The variant lies in a statistically significant hotspot.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in the general population.
The variant is an in-frame deletion-insertion that alters protein length (p.Gly12delinsCysAla) in a non-repetitive region, consistent with a potential gain-of-function effect in the RAS/MAPK pathway.
No variant-specific functional studies, de novo observations, case reports, or segregation data were identified in the available literature or databases. OncoKB classifies this variant as Oncogenic with gain-of-function effect.
Insufficient evidence exists to reach a definitive classification under the RASopathy VCEP v2.3.0 framework. Met criteria: PM1 (Moderate), PM2 (Supporting), PM4 (Moderate). Key data gaps include absence of functional studies, patient phenotype data, and segregation analysis.
No criteria match.
Met · 3
PM1 ModerateThe variant affects codon 12 within the P-loop domain (amino acids 10-17), a critical and well-established functional domain per the RASopathy VCEP supplementary table. Codon 12 is a known mutational hotspot with no benign variation in this region. Hotspot analysis confirms this residue is statistically significant. Details ▾Hide ▴
Evidence considered
- P-loop domain includes AA 10-17 per VCEP
- codon 12 is a well-established hotspot
- variant position confirmed as statistically significant hotspot
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 SupportingThis variant is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per RASopathy VCEP v2.3.0, PM2 is applied at Supporting strength when the variant is absent from gnomAD controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0
Sources
PM4 ModerateThis is an in-frame deletion-insertion (c.34_35delinsTGTGC) resulting in a protein length change (p.Gly12delinsCysAla). KRAS has no known repetitive regions per the RASopathy VCEP. PM4 is applied at Moderate strength per VCEP rule: 'No known repetitive areas in gene. Use as described.' Details ▾Hide ▴
Evidence considered
- In-frame delins at codon 12 alters protein length
- no repetitive regions in KRAS per VCEP
Sources
Not met · 4 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change as a previously established pathogenic variant. This variant produces p.Gly12delinsCysAla, an in-frame insertion at codon 12, which does not match any known pathogenic missense change at this codon. No prior pathogenic variant with this amino acid change has been identified. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule requires same amino acid change
- p.Gly12delinsCysAla is a novel in-frame change not matching any known pathogenic variant
Sources
PP3 VCEP PP3 applies to missense variants with REVEL ≥0.7 or splicing impact matching disease mechanism. This is an in-frame indel, not a missense variant; REVEL and BayesDel scores are not available. SpliceAI predicts no significant splice impact (max delta score = 0.01). Neither computational criterion is satisfied. Details ▾Hide ▴
Evidence considered
- Not a missense variant
- REVEL not available
- SpliceAI max delta = 0.01
- no significant splice impact predicted
Sources
BA1 RASopathy VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). BA1 is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD populations
- AF = 0
- well below BA1 threshold of ≥0.05%
Sources
BS1 RASopathy VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. This variant is absent from all gnomAD populations (allele frequency = 0). BS1 is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- AF = 0
- well below BS1 threshold of ≥0.025%
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo observations for this specific variant were identified in the available literature or ClinVar submissions. PS2 requires confirmed de novo occurrence in a patient with RASopathy phenotype. Details ▾Hide ▴
Evidence considered
- No de novo data available for NM_033360.3:c.34_35delinsTGTGC
Still missing
- No de novo reports available for this variant
PS3 No variant-specific functional studies for NM_033360.3:c.34_35delinsTGTGC were identified. OncoKB classifies this variant as Oncogenic, but this is a curated knowledgebase label rather than direct functional assay evidence. The only available publication (PMID:24642870) characterized different KRAS insertion variants (c.30_31insGGA, c.33_34insGGAGCT), not this specific variant. VCEP-approved assays (RAS Activation, MEK Activation, ERK Activation) have not been applied to this variant. Details ▾Hide ▴
Evidence considered
- OncoKB labels variant as Oncogenic (gain-of-function) but no direct variant-specific functional assay data available
Still missing
- No variant-specific functional assay data from VCEP-approved assay types
Sources
PS4 No patient case data or case-control studies involving this variant were identified. The variant is absent from ClinVar with no submissions from clinical laboratories. PS4 point-based scoring requires proband counts per VCEP specifications. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no proband counts available for PS4 point-based scoring
Still missing
- No case-control or proband data available
Sources
PM6 No assumed de novo observations for this variant were identified. PM6 point-based scoring requires de novo proband data per the SVI recommendations cited by the RASopathy VCEP. Details ▾Hide ▴
Evidence considered
- No de novo data available for PM6 scoring
Still missing
- No de novo reports available
PP1 No co-segregation data for this variant was identified in the available literature. PP1 requires segregation analysis in affected family members; ≥3 informative meioses for Supporting, ≥5 for Moderate, ≥7 for Strong per VCEP. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation data available
BS2 No data regarding observation of this variant in healthy adult individuals was available. BS2 point-based scoring requires phenotypic information about heterozygous or homozygous carriers. Details ▾Hide ▴
Evidence considered
- No healthy individual carrier data available
Still missing
- No healthy carrier or population screening data
BS4 No segregation data was available to assess lack of segregation in affected family members. BS4 requires only one informative meiosis showing lack of segregation per VCEP. Details ▾Hide ▴
Evidence considered
- No family segregation data available to assess BS4
Still missing
- No segregation data available
BP2 No data regarding observation of this variant in trans with a pathogenic variant or cis with a pathogenic variant was available. BP2 point-based scoring requires evidence of an alternative molecular cause in the same gene. Details ▾Hide ▴
Evidence considered
- No data on variant phase with other pathogenic variants
Still missing
- No phase or co-occurrence data available
BP5 No data regarding an alternative molecular cause of RASopathy was available. BP5 point-based scoring requires evidence of an alternative molecular cause in a different gene with phenotype consistent with RASopathy severity. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause data available
Still missing
- No data on alternative molecular diagnosis
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable per ClinGen RASopathy VCEP v2.3.0 specifications; variant is an in-frame deletion-insertion, not a null variant (nonsense, frameshift, or canonical splice site). Details ▾Hide ▴
PM5 N/AVCEP PM5 rule applies to missense changes at the same codon where a different pathogenic missense change has been established. This variant is an in-frame deletion-insertion, not a missense change. Per PM5 candidate analysis, the variant class is not missense-like and is not eligible for classic same-residue PM5. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- not a missense change
- PM5 candidate analysis confirms not eligible
Sources
cspec ↗pm5_candidates
PP2 VCEPNot applicable per RASopathy VCEP v2.3.0. The missense z-score for KRAS is <3.09 in gnomAD, so PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- VCEP marks PP2 as Not applicable: missense z-score <3.09 in gnomAD
Sources
PP4 VCEPNot applicable per RASopathy VCEP v2.3.0. PP4 is superseded by PS4 and is not separately evaluated in this framework. Details ▾Hide ▴
PP5 VCEPNot applicable for this VCEP per ClinGen RASopathy VCEP v2.3.0; the VCEP Review Committee recommends against use of PP5. Details ▾Hide ▴
BS3 VCEPNot applicable per RASopathy VCEP v2.3.0. BS3 (well-established functional studies showing no damaging effect) is marked as Not applicable by the VCEP. Details ▾Hide ▴
BP1 N/ARASopathy VCEP BP1 applies to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, exon/gene deletion) in genes where RASopathies have a gain-of-function mechanism. This variant is an in-frame deletion-insertion, not a truncating variant. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- not a truncating variant
- BP1 applies only to truncating variants
Sources
BP3 VCEPNot applicable per RASopathy VCEP v2.3.0. No known benign repetitive areas exist in RASopathy genes, and BP3 is specific to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴
Evidence considered
- VCEP marks BP3 as Not applicable: no known benign repetitive areas in RASopathy genes
Sources
BP4 N/ARASopathy VCEP BP4 applies to missense variants with REVEL ≤0.3 or splicing variants with no predicted impact matching disease mechanism. This is an in-frame indel; REVEL is not available and BP4 is not applicable to non-missense, non-splice variants. Details ▾Hide ▴
Evidence considered
- Not a missense variant
- REVEL not available
- BP4 not applicable to in-frame indels
Sources
BP6 VCEPNot applicable for this VCEP per ClinGen RASopathy VCEP v2.3.0; the VCEP Review Committee recommends against use of BP6. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame deletion-insertion at codon 12, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- not synonymous
- BP7 is for silent variants only
Sources
PS5 N/ANot applicable for this VCEP per ClinGen RASopathy VCEP v2.3.0; the VCEP Review Committee recommends against use of PP5. Details ▾Hide ▴
Identifiers
- Gene
- KRAS
- Transcript
- NM_033360.3
- Coding (HGVS c.)
- NM_033360.3:c.34_35delinsTGTGC
- Protein (HGVS p.)
- NP_203524.1:p.(Gly12delinsCysAla)
- GRCh38
- chr12:25245350 CC>GCACA
- GRCh37
- chr12:25398284 CC>GCACA
Gene diagram
Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.3. Select a row to find it on the plot.
KRASNM_033360.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 VCEP PP3 applies to missense variants with REVEL ≥0.7 or splicing impact matching disease mechanism. This is an in-frame indel, not a missense variant; REVEL and BayesDel scores are not available. SpliceAI predicts no significant splice impact (max delta score = 0.01). Neither computational criterion is satisfied. Details ▾Hide ▴
Evidence considered
- Not a missense variant
- REVEL not available
- SpliceAI max delta = 0.01
- no significant splice impact predicted
Sources
BP4 N/ARASopathy VCEP BP4 applies to missense variants with REVEL ≤0.3 or splicing variants with no predicted impact matching disease mechanism. This is an in-frame indel; REVEL is not available and BP4 is not applicable to non-missense, non-splice variants. Details ▾Hide ▴
Evidence considered
- Not a missense variant
- REVEL not available
- BP4 not applicable to in-frame indels
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame deletion-insertion at codon 12, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is an in-frame delins
- not synonymous
- BP7 is for silent variants only
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 24642870 ↗Characterization of rare transforming KRAS mutations in sporadic colorectal cancer.Characterizes rare KRAS insertion mutations in 1,506 colorectal cancer patients. Two in-frame insertion mutations were identified: c.30_31insGGA (p.G10_A11insG) and c.33_34insGGAGCT (p.A11_G12insGA). NM_033360.3:c.34_35delinsTGTGC (p.Gly12delinsCysAla) was not identified in this paper.Does not name this variant
Quoted passage
Two rare in-frame insertion mutations in this study, c.30_31insGGA: p.G10_A11insG (duplication of codon 10) and c.33_34insGGAGCT:p.A11_G12insGA
Table of KRAS mutations; Results section describing insertion variants
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243114
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_033360.3%3Ac.34_35delinsTGTGC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-25398284-CC-GCACA?dataset=…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-25245350-CC-GCACA?datas…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-25245350-CC-GCACA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033360.3%3Ac.34_3…
- OncoKB ↗www.oncokb.org/gene/KRAS/G12delinsCA
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KRAS+c.34_35delinsTGTGC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.